Selected Problems in Diagnosis Background to Thyroid Neoplasia - - PowerPoint PPT Presentation

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Selected Problems in Diagnosis Background to Thyroid Neoplasia - - PowerPoint PPT Presentation

Dec 12, 2022 316 likes •570 views

Challenges in the Diagnosis of Thyroid Cancer An Update Speaker Disclosure No Dislosures to make. WC Faquin, M.D., Ph.D. William C. Faquin, M.D., Ph.D. Director, Head and Neck Pathology Massachusetts General Hospital & Massachusetts

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Challenges in the Diagnosis of Thyroid Cancer – An Update

William C. Faquin, M.D., Ph.D. Director, Head and Neck Pathology Massachusetts General Hospital & Massachusetts Eye and Ear Infirmary Boston, MA Speaker Disclosure No Dislosures to make.

WC Faquin, M.D., Ph.D.

Selected Problems in Diagnosis

*Min. invasive follicular carcinoma * Variants of papillary thyroid carcinoma * Poorly differentiated thyroid carcinoma

THYROID

Background to Thyroid Neoplasia

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  • Most common malignancy of endocrine system
  • Annual incidence = 122,000 cases worldwide
  • Young and middle-age adults
  • More common in women (2-4x; 1:120 risk in U.S.)
  • >90% 10 year survival

THYROID CARCINOMA The Overdiagnosis of Thyroid Carcinoma

Ahn et al N Engl J Med (2014)

15X increa se

Aggressive Thyroid Cancer

  • Less focus on malignant vs benign (NIFT)
  • More focus on identifying aggressive forms of

thyroid cancer

  • How to define aggressive thyroid carcinoma?

– Microscopic analysis is mixed:

  • Works well for UTC, less well for PDTC, unsat. for DTC

– Need for molecular indicators

Follicular adenoma vs. minimally invasive follicular carcinoma

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Follicular Adenoma vs “Hyperplastic”

  • Variety of names for benign follicular nodules:

– Follicular adenoma – Adenomatous nodule – Adenomatoid nodule – Hyperplastic nodule

  • Up to 60% of nodules in multinodular goiters

have been shown to be clonal

  • Follicular adenoma at MGH:

– Solitary or dominant, well-defined fibrous capsule, histologically different from surrounding normal.

Follicular Adenoma

PROCESSING SOLITARY THYROID NODULES For a single or dominant thyroid nodule, submit the entire capsule. FOLLICULAR ADENOMA

Histologic variants:

  • Toxic adenoma
  • Adenoma with papillary

hyperplasia

  • Adenoma with bizarre nuclei
  • Signet-ring adenoma
  • Adenoma with spindle cell

metaplasia

  • Adenolipoma/adenochondroma
  • Hurthle cell adenoma
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Follicular Adenoma With Adipose Tissue: Lipoadenoma

Follicular Adenoma With Bizarre Nuclei: Can Mimic Anaplastic or PD carcinoma

Follicular Adenoma With Signet Ring Cells: Can Mimic Metastatic Disease Follicular Adenoma With Spindle Cell Metaplasia: Can Mimic Medullary Carcinoma

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FOLLICULAR CARCINOMA

FOLLICULAR CARCINOMA

Two distinct histologic types:

  • Minimally invasive (COMMON)

up to 98% 10-year survival

  • Widely invasive (RARE)

30-45% 10-year survival Often shows “poorly differentiated histologic features”

WIDELY INVASIVE FOLLICULAR CARCINOMA MINIMALLY INVASIVE FOLLICULAR CARCINOMA

Histology:

Thick, irregular capsule Microfollicular, trabecular, or solid patterns Unequivocal transcapsular and/or angioinvasion

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Minimally Invasive Follicular Carcinoma

FOLLICULAR CARCINOMA

Capsular Invasion:

  • Full thickness invasion through capsule
  • “Mushrooming” appearance
  • New fibrous capsule along leading edge

Transcapsular Invasion

Transcapsular Invasion with Mushroom Appearance

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Mimic: Incomplete Capsular Invasion

Mimic: FNA ARTIFACT

Small capillaries, hemosiderin, fibrosis

Mimic: Vessel entering capsule:

Get Levels!

Follicular Carcinoma with Angioinvasion

Angioinvasion:

Considered by some a more reliable sign of

malignancy

Vessel is within or immediately outside the

capsule - Vessels within the tumor do not count!

Intravascular tumor covered by endothelial layer

  • r associated with thrombus

I do not require thrombus to be present!

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Minimally invasive follicular carcinoma = Grossly encapsulated follicular carcinoma with angioinvasion FOLLICULAR CARCINOMA

Endothelial lining Attached to vessel wall

Mimic: Artifactual tumor within ectatic vessel Mimic: Artifactual retraction of tissue

IHC for CD34 & TTF1

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Tips/Comments for Problem Cases: Invasion versus Artifact

Deeper H&E levels x 3 will resolve the

problem in a majority of cases

Is “atypical” or “uncertain malignant

potential” an option? Yes, but….

What about Hurthle cell tumors? Be cautious with tumors over 3 cm! Solid and trabecular HC tumors Mitotically active HC tumors

EXTRATHYROIDAL EXTENSION: Be Conservative!

Extrathyroidal extension = T3 Extension into surrounding muscle,

fibrovascular, and neural tissues

Significance of extension into perithyroidal

adipose tissue is uncertain (minimal EE)

Unreliable in the isthmus

Selected Challenges in the Diagnosis

  • f Papillary Thyroid Carcinoma

PAPILLARY THYROID CARCINOMA

70-80% of thyroid carcinomas Indolent (although certain variants are aggressive) - <6.5% mortality Young to middle-aged (20-50 years) Women:men (4:1) Prior radiation exposure, Hashimoto thyroiditis, 4-fold increase among offspring of affected

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Frozen Section: To Freeze or Not to Freeze???

–At the MGH, a subset of thyroidectomy specimens are sent for frozen section: »Limited to those that were indefinite for PTC by FNA »Many frozen section pitfalls!!! –Intraoperative smears are routinely performed to compliment the frozen section

To Freeze or Not to Freeze???

Can easily be mistaken for PTC in frozen section

Artifactual inclusion

Cytology of Papillary Thyroid Carcinoma

Oval, pale, grooved nuclei

PAPILLARY THYROID CARCINOMA: Many Variants!

Variants:

  • Encapsulated
  • Follicular
  • Macrofollicular
  • Diffuse sclerosing
  • Warthin-like
  • Solid
  • Trabecular
  • Cribriform-Morular
  • Oncocytic
  • Hobnail
  • Tall cell
  • Columnar cell
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It is important to recognize certain variants of PTC: *May pose a diagnostic problem

*May be associated with syndromes such as FAP *May suggest an aggressive clinical behavior.

PAPILLARY THYROID CARCINOMA

Follicular variant:

  • Most common variant: 10-15% of PTC
  • RAS mutations are most common
  • Many are encapsulated - NIFT
  • The DDX is with follicular adenoma

Histologic Features: Classic PTC nuclear features (Subtle in 30% of cases): Pale oval nuclei Crowded/overlapping nuclei Longitudinal nuclear grooves Intranuclear pseudoinclusions are RARE Small amounts of dense hypereosinophilic colloid Intraluminal histiocytes/giant cells

Easily Recognizable FVPTC

Nuclear Overlap

FVPTC: Irregularly spaced & overlapping oval nuclei

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Encapsulated FVPTC:

Many nuclear grooves, nuclei are somewhat hyperchromatic Abortive Papilla

FVPTC: A Good Clue….

Overlapping oval nuclei and abortive papillae

Hypereosinophilic Colloid Multinucleate Histiocytes in lumen

Clues to FVPTC:

Immunohistochemical Markers to Help Diagnose FVPTC: Galectin-3, CD117, and HBME-1

Galectin-3+ CD117-

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  • Sample the capsule well to search for invasion
  • Get levels x 3 on blocks with susp for invasion
  • Compare nuclear features to surrounding normal

thyroid tissue

  • Search for nuclear overlap, intraluminal

histiocytes, and abortive papillae

  • Last resort: galectin-3+, HBME-1+, CD117 –
  • Molecular features are generally not useful

The Follicular Variant of Papillary Carcinoma

In over 1/3 of cases, the encapsulated/ non-invasive FVPTC can pose a significant diagnostic challenge!

The Follicular Variant of Papillary Carcinoma

A consensus group of thyroid experts led by

  • Dr. Nikiforov is drafting a recommendation to suggest:

Non-Invasive Follicular Thyroid (NIFT) Neoplasm with Papillary-Like Nuclear Features

NIFT NIFT

Solves an important thyroid pathology issue

Redefines a large set of low-risk cancers as “neoplasms” [or “uncertain malignant potential”]

Non-invasive Follicular-patterned Dx is independent of molecular profile

Pax8-PPARg, RAS, BRAF

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NIFT

Non-invasive: encapsulated, partially encapsulated, unencapsulated Risk of malignant behavior is low Low metastatic potential (0%) Vivero et al 2013 Low recurrence risk (3%) Management would likely be lobectomy alone

Encapsulated FVPTC - NIFT:

Mild nuclear overlap and grooves

NIFT

Manuscript in preparation Validation/comment period ?Role of molecular studies Reassessment of FNA and ROM Implications for medicolegal risk

Four variants of PTC that are often more aggressive, but NOT independent predictors of an aggressive behavior.

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PAPILLARY THYROID CARCINOMA

Hobnail Variant:

  • Rare aggressive variant
  • Average age 54 years
  • Female predominance
  • 63% Stage III or IV at presentation
  • Large size, extrathyroidal extension, LN mets
  • Subset with tall cell features or UTC
  • BRAF+ in 80% of cases; RET/PTC in 20%

Hobnail Variant of PTC Hobnail Variant of PTC: Cells often are dyshesive Hobnail Variant of PTC: Cells show a clinging pattern

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Hobnail Variant of PTC:

Nuclei tend to be more hyperchromatic than classical PTC

PAPILLARY THYROID CARCINOMA

Diffuse Sclerosing Variant:

  • Uncommon
  • Occurs in children and young adults
  • Widely invasive with extrathyroidal extension
  • RET-PTC rearrangements most common
  • More aggressive than conventional PTC:

LN mets & frequent distant mets.

Lymphoid stroma Lymphatic with tumor

Diffuse Sclerosing PTC: Extensive Lymphatic Involvement

Sclerosis

Diffuse Sclerosing PTC: Diffuse involvement and dense sclerosis

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Psammoma body

Diffuse Sclerosing PTC: Many Psammoma Bodies Diffuse Sclerosing PTC: Squamous Morules

Pitfall: Avoid misinterpreting the usual stromal hyalinization of PTC as DSV.

  • Tall cell variant:
  • Uncommon
  • Elderly patients
  • Large size (usually >5.0 cm)
  • Often more aggressive than conventional PTC
  • BRAF mutations common

PAPILLARY THYROID CARCINOMA

Histologic Features:

>50% tall cylindrical cells (2-3x tall as wide) Papillary fronds of cells Abundant acidophilic (pink) cytoplasm Basally-located nuclei with conventional PTC

nuclear features

Mitotic activity and necrosis

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Tall Cell Variant of PTC: Cells are 2-3x as tall as wide Tall Cell Variant of PTC TCV PTC: Mitoses and Tumor Necrosis are Common

If the tall cell component is less than 50%, we use the term “PTC with tall cell features.”

Tall Cell Variant of PTC

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Columnar Cell Variant of PTC: Resembles an Intestinal Neoplasm Columnar Cell Variant of PTC: Feathered Appearance of Columnar Cells Columnar Cell Variant of PTC: Often Includes Squamous Morules

Diagnosing poorly differentiated thyroid carcinoma

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Poorly Differentiated Thyroid Carcinoma

Insular type is the classic form

  • Approx. 4% of thyroid carcinomas

Mean survival = 3.9 years Metastasis to LN, lung, bone, liver, brain Poor prognosis even when encapsulated or focal An aggressive subset contains ALK gene rearrangements or TERT mutations

NEOPLASMS OF FOLLICULAR CELLS

Minimally invasive follicular Minimally invasive Hurthle cell Papillary (most variants) Insular Solid Trabecular Spindle Giant cell Squamoid T(2;3)(q13;p25) RET/PTC BRAF RAS P53 B-catenin TERT ALK MORTALITY: 2-8% 3-50% >95%

BENIGN

P53 Ki-67 TERT ALK

Poorly Differentiated Carcinoma with Characteristic Insular Pattern Poorly Differentiated Carcinoma with Extensive angioinvasion is often present

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Poorly Differentiated Carcinoma with High N/C ratio cells

Frequent mitoses

ATYPIA Microfollicles Necrosis

Poorly Differentiated Carcinoma

  • Can arise de novo or in association with

a well differentiated carcinoma

  • Can be a precursor of anaplastic

carcinoma.

Insular Carcinoma and Papillary Thyroid Carcinoma

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PD Carcinoma and Follicular Carcinoma

PD Carcinoma and Anaplastic Carcinoma

Even when focal, a poorly differentiated component should be mentioned in the pathology report.

Poorly Differentiated Thyroid Carcinoma

Poorly Differentiated Thyroid Carcinoma

  • Medullary carcinoma
  • Metastatic neuroendocrine

carcinoma

  • Solid variant of papillary

carcinoma DDX:

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Poorly Differentiated Thyroid Carcinoma

  • Positive for thyroglobulin, TTF-1, &

PAX-8

  • Shows increased reactivity for MIB-1

and p53

  • Usually negative for neuroendocrine

markers

  • Negative for calcitonin
  • + B-catenin

Ancillary Markers:

Thyroglobulin +

The Turin Proposal for Diagnosing Poorly Differentiated Thyroid Carcinoma

The Turin Proposal

Malignant follicular neoplasm Solid, trabecular or insular growth pattern Absence of conventional nuclear features of papillary carcinoma Presence of at least one of the following:

Convoluted nuclei Mitotic activity > 3 per 10 HPF Tumor Necrosis

Necrosis Convoluted Nuclei

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The Turin Proposal

Does not account for encapsulated non-invasive forms Does not account for “high grade” forms of PTC More markers needed to distinguish the bad actors - ? TERT and ALK

SUMMARY

  • Use deeper H&E levels liberally in the

assessment of capsular and angioinvasion

  • Beware of certain variants of PTC which

can cause a diagnostic pitfall or are more aggressive

  • Prepare for the arrival of NIFT
  • Poorly differentiated thyroid carcinoma

should be recognized and reported even when focal

  • Longterm goal: More emphasis on

aggressive disease and less overdiagnosis of indolent cancer!

Thank You!